(-)-Galanthamine is a tertiary Amaryllidaceae alkaloid having acetylcholinesterase inhibitor properties thereby enhancing cholinergic function. The cholinesterase inhibitors have recently been under investigation for use as nootropics, in particular, in the treatment of Alzheimer's disease. Currently, galanthamine is only available through an extraction from daffodils (Narcissus Pseudonarcissus L.). The extraction process has proved to be quite expensive for pharmaceutical grade material, even when taking into account large scale production efficiencies.
An alternate source of (-)-galanthamine is its chemical synthesis. Some synthetic routes to galanthamine have been published over the last 30 years, beginning with the work of Barton and Kirby in 1962 (J. Chem. Soc. 1962, 806). Over the years, other contributors to synthetic steps in the production of galanthamine from readily available materials have included Shimizu et at, Heterocycles 1977, 8, 277; and Shimizu et at, Chem. Pharm. Bull. 1978, 26, 3765. Additional contributions to the production of racemic galanthamine (which would still need to be resolved) have: been made by Szewczyk et at, J. Heterocycl. Chem., 1988, 25, 1809; Karnetani et at, J. Org. Chem. 1971, 36, 1295; Kametani et al, J. Chem. Soc. Perkin Trans. 1, 1972, 1513; Kametani et al, J. Heterocycl. Chem. 1973, 10, 35; Vlahov et al, Tetrahedron 1989, 45, 3329; and Holton et al, J. Am. Chem. Soc. 1988, 110, 314. Holton's work provided a short and elegant synthesis of racemic narwedine; (-)-narwedine is the biogenic precursor of (-)-galanthamine. Notwithstanding these advances, the synthetic approach to (-)-galanthamine production in high purity pharmaceutical grade on a commercial scale is still problematical.
In 1962 Barton et al reported the first successful chemical synthesis of (-)-galanthamine by reducing (-)-narwedine, which itself was obtained by chemical resolution on a small laboratory scale. Barton's process was able to yield racemic narwedine in an amount of about 1.4%. Banon then reduced the racemic narwedine with lithium aluminum hydride and obtained both racemic galanthamine and racemic epigalanthamine. Banon further reported that the Ponndorf-Meerwein reduction of racemic narwedine gave mostly racemic epigalanthamine. In the course of oxidizing (-)-galanthamine (obtained from extraction or other sources) to narwedine (to confirm structures), Banon found that the presence of some unoxidized (-)-galanthamine remaining in the oxidation product mixture resulted in (+)-narwedine, rather than racemic narwedine. Reduction of this gave (+)-galanthamine and (+):epigalanthamine. These were then used as is to resolve racemic narwedine to obtain the (-) compound. On obtaining the (-)-narwedine, Banon then reduced the material to obtain a mixture of (-)-galanthamine and (-)-epigalanthamine. Typically, the reduction reported by Barton resulted in about 40% of the yield being epigalanthamine.
According to Banon, the greater the amount of enantiomeric galanthamine used, the better the resolution of narwedine. Basically, the Banon process took racemic narwedine and used some (-)-galanthamine to produce (+)-narwedine. This was then reduced to the (+)-galanthamine and (+)-epigalanthamine, which were then used to convert additional racemic narwedine to (-)-narwedine, which would be reduced to (-)-galanthamine and (-)-epigalanthamine. Clearly, this was an extremely wasteful process and not very suitable to large scale production.
At page 810 of the Banon et al article, the authors report that the standard resolution techniques were not successful, whether applied to narwedine or galanthamine, therefore making the above complicated process necessary to achieve (-)-galanthamine through synthetic means.
Szewczyk et at, in J. Heterocyclic Chem. 25, 1809 (1988), disclose an alternate process which goes through a narwedine analog yielding about 50% racemic galanthamine and about 30% racemic epigalanthamine. Kametani et al, J. Org. Chem. 36, No. 9, 1971, 1295-1297, also report still another synthesis. Both of these references utilize lithium aluminumhydride as the reducing agent to reduce the precursor to galanthamine. In each case, racemic material is obtained as a mixture of both galanthamine-and epigalanthamine. The two Shimizu et al articles relate; complex synthetic mutes to enantiomeric galanthamine (not really related to the present processes) in fairly low overall yield.
As mentioned above, Holton et al reported a short, elegant synthesis of racemic narwedine in 1988.
Notwithstanding all of these researchers attempting to find an economic, scalable, synthetic route for (-)-galanthamine, none has been adequately found. Either the processes are so involved as to make the overall yields totally unacceptable or too expensive, or the processes end in the need to resolve the racemates or in the inefficient concomitant production of substantial amounts of epigalanthamine.